Parkinson's disease is a slowly progressive degenerative disorder with classic motor symptoms that include resting tremor, cogwheel rigidity and bradykinesia. The disease produces invariant loss of dopamine neurons in the substantia nigra (SN) with the hallmark pathological features of activated microglia and proteinaceous cytoplasmic inclusions called Lewy bodies in the remaining neurons. Epidemiological data supports that gene-environment interactions are responsible for the largest proportion of sporadic PO cases. One of the key issues in PO is the identification of the initiating triggering mechanism(s) and the locus of its injury. Efforts to elucidate th[unreadable]ls mechanism have been aided by the linkage between toxicant (e.g., MPTP, paraquat. rotenone) injury, oxidative stress, inherited defects in turnover of the presynaptic and Lewy Body constituent protein a-synuclein (SYN), and involvement of cytosolic dopamine. Using established animal models of wild-type (wtSYN+/+) and mutant SYN (dmSYN+/+) overexpression in OA producing cells we will address the hypothesis that an early effect of SYN overexpression is increased microglial activation and proinflammatory processes leading to presynaptic dysfunction. We further posit that wtSYN and dmSYN activate microglia differentially but both result in an increased quinone oxidant response. Three aims are proposed to test this hypothesis: Ai m 1. Characterization of microglial activation and presynaptic function in mice overexpressing wild-type (wtSYN+/+) or double-mutant SYN (dmSYN+/+); Aim 2. Characterization of the proinflammatory response to wtSYN and dmSYN: Aim 3. Examination of the role of quinone-mediated oxidative stress in microglial activation. We will utilize several unique transgenic mouse models including wtSYN+/+ that overexpress wIld-type SYN, dmSYN+/+ that overexpress mutant SYN, wtSYN+/+::AREhPLAP and dmSYN+/+::AREhPlAP which overexpress SYN in the background of a mouse capable of reporting quinone-mediated stress. These studies will produce clear and interpretable data concerning the role of microglia in the presynaptic injury elicited by SYN. Parkinson 's Disease (PO) is the second most common neurodegenerative disease and impacts both patients and their caregivers. The goal of this project is to evaluate the progressive changes in the brain during PD. We focus our work on both tissue culture and animal models of PO and ask what is the role of pro-inflammatory molecules and microglia in disease initiation and progression . Particularly we will study early changes in PD. The results of these studies may lead to the identIfication of potential therapies for PD.